Overproduction of NOX-derived ROS in AML promotes proliferation and is associated with defective oxidative stress signaling

摘要: Excessive production of reactive oxygen species (ROS) is frequently observed in cancer and known to strongly influence hematopoietic cell function. Here we report that extracellular ROS elevated (mean >10-fold) >60% acute myeloid leukemia (AML) patients this increase attributable constitutive activation nicotinamide adenine dinucleotide phosphate oxidases (NOX). In contrast, overproduction mitochondrial was rarely observed. Elevated found be associated with lowered glutathione levels depletion antioxidant defense proteins. We also show for the first time generated were able promote proliferation AML lines, primary blasts, and, a lesser extent, normal CD34+ cells, response limited by oxidative stress pathway mediated though p38MAPK. Consistent this, p38MAPK responses attenuated expressing high ROS. These data NOX-derived can blasts they develop mechanisms suppress signaling would normally limit response. Together these adaptations predicted confer competitive advantage leukemic clone.